Effect of spinal monoaminergic neuronal system dysfunction on pain threshold in rats, and the analgesic effect of serotonin and norepinephrine reuptake inhibitors

Tamano, Ryuta; Ishida, Mitsuhiro; Asaki, Toshiyuki; Hasegawa, Minoru; Shinohara, Shunji

doi:10.1016/j.neulet.2016.01.025

Cited by 33 publications

(17 citation statements)

References 36 publications

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“…Furthermore, duloxetine presented a special effect and superior performance compared with the placebo in moderate and substantial pain improvements at the end‐point. This may be attributed to the direct analgesic effect of duloxetine through enhancing the descending spinal pain modulatory pathways by inhibiting the reuptake of serotonin and norepinephrine, regardless of its antidepressant actions . Preclinical studies have shown that duloxetine can alleviate the symptom of pain within a series of persistent, inflammatory, and neurological pain models through an analgesic mechanism .…”

Section: Discussionmentioning

confidence: 99%

“…This may be attributed to the direct analgesic effect of duloxetine through enhancing the descending spinal pain modulatory pathways by inhibiting the reuptake of serotonin and norepinephrine, regardless of its antidepressant actions. 15,28 Preclinical studies have shown that duloxetine can alleviate the symptom of pain within a series of persistent, inflammatory, and neurological pain models through an analgesic mechanism. [29][30][31] Moreover, in a previous pooled analysis, subgroup analyses of older and younger participants were conducted to determine whether duloxetine had different analgesic effects; it demonstrated that there was no statistically significant difference.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy and tolerability of duloxetine in patients with knee osteoarthritis: a meta‐analysis of randomised controlled trials

Chen

Gong

Liu

et al. 2019

Internal Medicine Journal

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Background Knee osteoarthritis (OA) is one of the most common joint diseases, and pharmacotherapy is necessary to control its symptoms. Aim To evaluate efficacy and tolerability of duloxetine in patients with knee OA. Methods PubMed, Web of Science, Embase, Cochrane Library and http://ClinicalTrials.gov were searched to identify randomised controlled trials comparing duloxetine with placebo for knee OA. Data including pain, stiffness, physical function, and adverse events were extracted for meta‐analysis. The protocol was prospectively registered in PROSPERO (CRD42018097110). Results Data from six randomised controlled trials including 2059 participants were pooled. Duloxetine achieved significant reductions in primary outcomes including Brief Pain Inventory 24‐h average pain score (weighted mean difference (WMD) = −0.74, 95% confidence interval (CI) = −0.92 to −0.57), weekly mean of the 24‐h average pain score (WMD = −0.76, 95% CI = −0.96 to −0.56), WOMAC stiffness score (WMD = −0.47, 95% CI = −0.60 to −0.34) and WOMAC physical function score (WMD = −4.44, 95% CI = −5.24 to −3.64). Furthermore, duloxetine demonstrated a higher number of treatment‐emergent adverse events (risk ratio (RR) = 1.31, 95% CI = 1.20–1.44) and discontinuations (RR = 2.26, 95% CI = 1.63–3.12); however, no difference in serious adverse events (RR = 0.92, 95% CI = 0.40–2.11) was observed. Conclusion Duloxetine is effective in the management of chronic pain and loss of physical function in knee OA with acceptable adverse events despite having no advantage in treating joint stiffness. Future trials should focus on determining the optimal treatment regimen.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Efficacy and tolerability of duloxetine in patients with knee osteoarthritis: a meta‐analysis of randomised controlled trials

Chen

Gong

Liu

et al. 2019

Internal Medicine Journal

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“…) including potential spinal cord actions (Tamano et al . ). Tramadol and tapentadol have mixed mu opioid receptor and reuptake inhibitory actions, the former with dual NA–5‐HT re‐uptake actions, the latter with NA only (Raffa et al .…”

Section: Introductionmentioning

confidence: 97%

The plasticity of descending controls in pain: translational probing

Bannister

Dickenson

2017

The Journal of Physiology

138

112

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Descending controls, comprising pathways that originate in midbrain and brainstem regions and project onto the spinal cord, have long been recognised as key links in the multiple neural networks that interact to produce the overall pain experience. There is clear evidence from preclinical and clinical studies that both peripheral and central sensitisation play important roles in determining the level of pain perceived. Much emphasis has been put on spinal cord mechanisms in central excitability, but it is now becoming clear that spinal hyperexcitability can be regulated by descending pathways from the brain that originate from predominantly noradrenergic and serotonergic systems. One pain can inhibit another. In this respect diffuse noxious inhibitory controls (DNIC) are a unique form of endogenous descending inhibitory pathway since they can be easily evoked and quantified in animals and man. The spinal pharmacology of pathways that subserve DNIC are complicated; in the normal situation these descending controls produce a final inhibitory effect through the actions of noradrenaline at spinal α -adrenoceptors, although serotonin, acting on facilitatory spinal 5-HT receptors, influences the final expression of DNIC also. These descending pathways are altered in neuropathy and the effects of excess serotonin may now become inhibitory through activation of spinal 5-HT receptors. Conditioned pain modulation (CPM) is the human counterpart of DNIC and requires a descending control also. Back and forward translational studies between DNIC and CPM, gauged between bench and bedside, are key for the development of analgesic therapies that exploit descending noradrenergic and serotonergic control pathways.

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“…The amygdala CRF neurons are well situated for the role of pain switch because they not only receive and respond to nociceptive stimuli but also undergo plasticity in association with chronic nociceptive stimulation and are responsible for the central sensitization and hyperalgesia observed in chronic pain [19]. Furthermore, the CRF projections from the CeAmy to the LC provide a pathway by which information that reaches the amygdala can influence descending inhibition of pain [12, 23] and it has been well established that the LC and norepinephrine are essential for pain inhibition including SIA [24-26]. Still, the effects of chronic pain on norepinephrine signaling in the spinal cord are not clear with some reports demonstrating that chronic pain inhibits norepinephrine levels [27] and other showing that chronic pain enhances norepinephrine signaling in the spinal cord [28].…”

Section: Introductionmentioning

confidence: 99%

Contribution of amygdala CRF neurons to chronic pain

Andreoli

Marketkar

Dimitrov

2017

Experimental Neurology

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We investigated the role of amygdala corticotropin-releasing factor (CRF) neurons in the perturbations of descending pain inhibition caused by neuropathic pain. Forced swim increased the tail-flick response latency in uninjured mice, a phenomenon known as stress-induced analgesia (SIA) but did not change the tail-flick response latency in mice with neuropathic pain caused by sciatic nerve constriction. Neuropathic pain also increased the expression of CRF in the central amygdala (CeAmy) and ΔFosB in the dorsal horn of the spinal cord. Next, we injected the CeAmy of CRF-cre mice with cre activated AAV-DREADD (Designer Receptors Exclusively Activated by Designer Drugs) vectors. Activation of CRF neurons by DREADD/Gq did not affect the impaired SIA but inhibition of CRF neurons by DREADD/Gi restored SIA and decreased allodynia in mice with neuropathic pain. The possible downstream circuitry involved in the regulation of SIA was investigated by combined injections of retrograde cre-virus (CAV2-cre) into the locus ceruleus (LC) and cre activated AAV-diphtheria toxin (AAV-FLEX-DTX) virus into the CeAmy. The viral injections were followed by a sciatic nerve constriction ipsilateral or contralateral to the injections. Ablation of amygdala projections to the LC on the side of injury but not on the opposite side, completely restored SIA, decreased allodynia and decreased ΔFosB expression in the spinal cord in mice with neuropathic pain. The possible lateralization of SIA impairment to the side of injury was confirmed by an experiment in which unilateral inhibition of the LC decreased SIA even in uninjured mice. The current view in the field of pain research attributes the process of pain chronification to abnormal functioning of descending pain inhibition. Our results demonstrate that the continuous activity of CRF neurons brought about by persistent pain leads to impaired SIA, which is a symptom of dysregulation of descending pain inhibition. Therefore, an over-activation of amygdala CRF neurons is very likely an important contributing factor for pain chronification.

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Effect of spinal monoaminergic neuronal system dysfunction on pain threshold in rats, and the analgesic effect of serotonin and norepinephrine reuptake inhibitors

Cited by 33 publications

References 36 publications

Efficacy and tolerability of duloxetine in patients with knee osteoarthritis: a meta‐analysis of randomised controlled trials

Efficacy and tolerability of duloxetine in patients with knee osteoarthritis: a meta‐analysis of randomised controlled trials

The plasticity of descending controls in pain: translational probing

Contribution of amygdala CRF neurons to chronic pain

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